Cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are important second messengers in cell, and the level of cAMP and cGMP in cell is important to regulate various functions of the cell. Enzymes participated in regulating cAMP and cGMP level in cell include adenylate cyclase (AC), guanylate cyclase (GC) and phosphodiesterase (PDE). Balance coordination of these enzymes maintains the level of cAMP and cGMP in cell within normal ranges. In some disease states (e.g., hypertension, angina pectoris, etc.), it is found that the level of cAMP and cGMP in cell drops. To increase the level of cAMP and cGMP in cell, two options can be implemented: 1) to activate AC and GC, and 2) to inhibit PDE, in which the second option has better effects. In recent years, there is a great passion to study and develop PDE inhibitor, and clinical application of isoenzyme-selective PDE inhibitor has achieved breakthrough progress. Currently, the experimental results of cDNA molecule clone have proved that there are at least 10 kinds of PDE gene families in mammals. For each PDE gene family, there are a plurality of PDE isoenzyme subtypes due to splice variant, in which type 5 phosphodiesterase (PDE5) family can selectively hydrolyze cGMP, and is widely distributed in individual body organs.
PDE5 Inhibitor has the Following Pharmacological Functions and Clinical Applications:
(1) Inhibiting platelet aggregation and anti-thrombosis: ideal antithrombotic drugs shall inhibit platelet aggregation without relaxation of vascular smooth muscle, to avoid causing the ischemia site to become further ischemia. Both PDE3 and PDE5 inhibitors have the function of inhibiting platelet aggregation. However, in view that PDE5 inhibitor has reduced relaxation of vascular smooth muscle, it has substantial advantage in treating arterial thrombotic diseases. The typical PDE5 inhibitor—dipyriamole has good antithrombotic effects.
(2) Decreasing pulmonary hypertension and anti-cardiovascular diseases: abnormality of pulmonary vascular resistance often is an important factor to cause cardiovascular diseases. In animal model experiments, selective PDE5 inhibitor—zaprinast can substantially increase the effective time and intensity of nitric oxide, and has relatively strong effects to lower pulmonary hypertension. Clinically it is used to treat angina pectoris, hypertension and myocardial infarction. In the latest report, PDE5 inhibitor—E-4010 can increase the survival rate of rats having hypertension induced by monocrotaline.
(3) Anti-asthma: It is reported that experiments using pigs as animal model show that PDE5 inhibitor—SR-265579 has therapeutic effects to bronchiectasis induced by histamine;
(4) Treating diabetes gastroparesis: It is reported that to rats having diabetes, PDE5 inhibitor—sildenafil citrate can reverse delayed gastric emptying, and has certain therapeutic and improving effects to digestive system autonomic neuropathy complicated by diabetes.
(5) Treating erectile dysfunction: Since PDE5 is widely distributed in cavernous body of penis, PDE5 inhibitor can cause cGMP level in the cavernous body of penis to rise. Upon a series of physiological and biochemical reactions, the vascular smooth muscle is relaxed, and the penis erects. Unlike prostaglandin E1, PDE5 inhibitor will not cause pathologic erection, its function still needs sexual stimulus.